JP2009516675A - Isocysteine derivatives for treating pain - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein R ¹ , R ² , R ⁴ and R ^4a are as defined herein. The invention also relates to the use of a compound of formula (I) for the treatment of pain.
[Chemical 1]

Description

  The present invention relates to β-amino acid derivatives. More particularly, the present invention relates to thio-substituted β-amino acid derivatives as well as methods for preparing such derivatives, intermediates used in the preparation of such derivatives, compositions containing such derivatives, And the use of such derivatives.

  EP-A-0347000A discusses vanilloid derivatives useful for the treatment of herpes simplex infections. WO-A-99 / 65881 discusses heterocyclic derivatives useful as hypoglycemic agents. WO-A-01 / 56991 discusses substituted pyridine derivatives useful for controlling chemical synaptic transmission.

  Since the compounds of the present invention are alpha-2-delta (α2δ) receptor ligands (also known as alpha-2-delta ligands), they are useful in the treatment of many different diseases. An alpha-2-delta receptor ligand is a molecule that binds to any subtype of the human calcium channel alpha-2-delta subunit. Calcium channel alpha-2-delta subunits are available in many subtypes described in the literature (eg, type 1, J. Biol. Chem., 1996, 271 (10), 5768-76; types 2 and 3, J Membr.Biol., 2001, 184 (1), 35-43 and Mol.Pharmacol., 2001,59 (5), 1243-1248; and type 4, Mol.Pharmacol., 2002,62 (3), 485. ~ 496). Alpha-2-delta receptor ligands are sometimes known as GABA analogs.

  Among the known alpha-2-delta receptor ligands are marketed drugs such as gabapentin (sold under the trademark Neurontin) and pregabalin (sold under the trademark Lyrica). is there. Gabapentin is an anticonvulsant marketed for the treatment of epilepsy. Pregabalin is marketed for the treatment of neuropathic pain.

  Always providing new drugs that potentially have improved properties (eg greater potency, greater selectivity, better absorption from the gastrointestinal tract, greater metabolic stability and more favorable pharmacokinetic properties) is necessary. Other potential benefits include greater or smaller blood brain barrier penetration, lower toxicity and reduced incidence of side effects, depending on the disease targeted.

  Accordingly, the present invention provides a compound of formula (I) as a first embodiment A,

または薬学的に許容できるその塩もしくは溶媒和物を提供し、式中、
Ｒ^１は、水素または（Ｃ_１〜Ｃ_６）アルキルであり、
Ｒ^２は、
ａ）１個または複数の置換基Ｒ^３によって置換されていてもよい（Ｃ_２〜Ｃ_６）アルキル、
ｂ）各々が１個または複数の置換基Ｒ^３によって置換されているフェニル、ナフチルまたはベンジル、および
ｃ）１個または複数の置換基Ｒ^３によって置換されていてもよい（Ｃ_３〜Ｃ_８）シクロアルキルから選択され、
各Ｒ^３は、独立して、ハロゲン、シアノ、ニトロ、アミノ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、ヒドロキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アルキル、ハロ（Ｃ_１〜Ｃ_６）アルキル、ハロ（Ｃ_１〜Ｃ_６）アルコキシ、ハロ（Ｃ_１〜Ｃ_６）アルキルチオ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（ジ−（Ｃ_１〜Ｃ_６）アルキル）アミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アルキル、（ジ−（Ｃ_１〜Ｃ_６）アルキル）アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アシルオキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アルキルチオ、（Ｃ_１〜Ｃ_６）アルキルチオカルボニル、（Ｃ_１〜Ｃ_６）アルキルスルホニル、（Ｃ_１〜Ｃ_６）アルキルスルホニルアミノ、アミノスルホニル、（Ｃ_１〜Ｃ_６）アルキルアミノスルホニル、（ジ−（Ｃ_１〜Ｃ_６）アルキル）アミノスルホニル、（Ｃ_３〜Ｃ_８）シクロアルキル、Ｈｅｔ^１、フェニルおよびＨｅｔ^２から選択され、
Ｈｅｔ^１は、各々が独立して窒素、酸素およびイオウから選択される１または２個のヘテロ原子環員を含む５または６員の飽和または部分不飽和の複素環式基であり、前記環窒素原子は、（Ｃ_１〜Ｃ_６）アルキル置換基を有していてもよく、前記環イオウ原子は、１または２個の酸素原子を有していてもよく、
Ｈｅｔ^２は、（ａ）１〜４個の窒素原子または（ｂ）１個の酸素もしくは１個のイオウ原子および０、１もしくは２個の窒素原子のどちらかを含む５もしくは６員のヘテロアリール基であり、
Ｒ^４およびＲ^４ａは、独立して、水素またはメチルであるが、
ただし、化合物は、３−アミノ−２−（エチルチオ）−プロパン酸ではない。

Or a pharmaceutically acceptable salt or solvate thereof, wherein
R ¹ is hydrogen or (C ₁ -C ₆ ) alkyl;
R ² is
a) (C ₂ -C ₆ ) alkyl optionally substituted by one or more substituents R ³ ,
b) phenyl, naphthyl or benzyl each substituted by one or more substituents R ³ , and c) optionally substituted by one or more substituents R ³ (C ₃ -C ₈ ) Selected from cycloalkyl,
Each R ³ is independently halogen, cyano, nitro, amino, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) Alkynyl, hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkoxy, Halo (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylamino, (di- (C ₁ -C ₆ ) alkyl) amino, amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) Alkylamino (C ₁ -C ₆ ) alkyl, (di- (C ₁ -C ₆ ) alkyl) amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) _{acyloxy, (C} 1 _{~C 6)} acyloxy _(C 1 ~C _{6) alkyl, (C} 1 _{~C 6) acylamino, (C} 1 _{~C 6) alkylthio, (C} 1 _{~C 6) alkylthiocarbonyl, (C} 1 _{~C 6)} alkylsulfonyl, _{(C 1} -C ₆₎ alkylsulfonylamino, _{aminosulfonyl, (C} 1 -C ₆₎ alkylaminosulfonyl, (di - _(C 1 -C ₆₎ alkyl) _{aminosulfonyl, (C} 3 -C ₈₎ cycloalkyl, ^Het 1, Selected from phenyl and Het ² ;
Het ¹ is a 5- or 6-membered saturated or partially unsaturated heterocyclic group containing 1 or 2 heteroatom ring members each independently selected from nitrogen, oxygen and sulfur, wherein the ring nitrogen The atom may have a (C ₁ -C ₆ ) alkyl substituent, the ring sulfur atom may have 1 or 2 oxygen atoms,
Het ² is a 5- or 6-membered heteroaryl containing either (a) 1 to 4 nitrogen atoms or (b) 1 oxygen or 1 sulfur atom and 0, 1 or 2 nitrogen atoms Group,
R ⁴ and R ^4a are independently hydrogen or methyl,
However, the compound is not 3-amino-2- (ethylthio) -propanoic acid.

  In the above definition, halo means fluoro, chloro or bromo, preferably fluoro or chloro. Alkyl and alkoxy groups containing the requisite number of carbon atoms may be straight or branched unless otherwise specified. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In embodiment B, the invention provides a compound of formula (I), wherein R ² , R ³ , R ⁴ and R ^4a are as defined above in embodiment A, and R ¹ is hydrogen, or a pharmaceutical Its acceptable salt is provided.

In embodiment C, the invention relates to wherein R ¹ is as defined above in embodiment A or embodiment B and R ³ , R ⁴ and R ^4a are as defined above in embodiment A. , R ² is
a) (C ₂ -C ₆ ) alkyl optionally substituted by one or more substituents R ³ ,
b) phenyl substituted by one or more substituents R ³ , and c) selected from (C ₃ -C ₈ ) cycloalkyl optionally substituted by one or more substituents R ³ Provided is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. Most preferably, R ² is (C ₂ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, each optionally substituted by 1 or 2 substituents R ³ , or 1 or 2 Is substituted with the substituent R ³ of

In embodiment D, the invention relates to wherein R ¹ is as defined above in embodiment A or embodiment B, R ² is as defined above in embodiment A or embodiment C, and R ⁴ and R ^4a are as defined above in embodiment A, and each R ³ is independently halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) alkylthio, more preferably each R ³ is independently halogen, (C ₁ -C ₆ Or a compound of formula (I) selected from alkyl, (C ₁ -C ₆ ) alkoxy, trifluoromethyl, trifluoromethoxy and trifluoromethylthio, or a pharmaceutically acceptable salt thereof, or A solvate is provided.

In embodiment E, the invention relates to wherein R ¹ is as defined above in embodiment A or embodiment B, R ² is as defined above in embodiment A or embodiment C, and R A compound of formula (I), wherein ³ is as defined above in embodiment A or embodiment D and R ⁴ and R ^4a are hydrogen, or a pharmaceutically acceptable salt or solvate thereof To do.

  Specific preferred compounds according to the invention are the compounds listed in the Examples section below and their pharmaceutically acceptable salts and solvates.

  Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

  Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansylate, citrate, cyclamine Acid salt, edicylate, esylate, formate, fumarate, glucocept, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / Bromide, hydrogen iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate , Orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, sugar salt, stearate, succinate, tannic acid Salt, tartrate, salt Le salts include trifluoroacetate and Kishinoho salt (xinofoate) is.

  Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salt, arginine salt, benzathine salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, olamine salt, potassium salt, sodium salt, tromethamine salt and zinc Contains salt.

  Acid and base hemi-salts such as hemisulfate and hemi-calcium salts can also be formed.

  For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002) by Stahl and Wermuth.

Pharmaceutically acceptable salts of the compounds of formula (I) can be obtained by one or more of three methods, ie
(I) reacting a compound of formula (I) with the desired acid or base,
(Ii) using the desired acid or base to remove the acid or base labile protecting group from the appropriate precursor of the compound of formula (I) or to open the appropriate cyclic precursor, such as a lactone or lactam. Can be prepared by converting one salt of a compound of formula (I) to another by cyclization or (iii) reaction with a suitable acid or base or by a suitable ion exchange column .

  Usually, all three reactions are performed in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to nearly non-ionized.

  The compounds of the present invention may exist in a series of solid states from fully amorphous to fully crystalline. The term “amorphous” refers to a state in which the material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Usually, such materials do not give a characteristic X-ray diffraction pattern and exhibit the properties of a solid, but more formally described as a liquid. Upon heating, a change from solid to liquid properties, usually characterized by a secondary state change (“glass transition”), occurs. The term “crystalline” refers to a solid phase where the material has a regular ordered internal structure at the molecular level and gives a distinct X-ray diffraction pattern with distinct peaks. Such materials also exhibit liquid properties when fully heated, but the change from solid to liquid is usually characterized by a first order phase change ("melting point").

  The compounds of the invention may also exist in unsolvated and solvated forms. As used herein, the term “solvate” is used to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term “hydrate” is used when the solvent is water.

  A currently accepted classification system for organic hydrates is to define isolated sites, channels, or metal ion coordination hydrates; R. See Polymerism in Pharmaceutical Solids by Morris (edited by HG Brittain, Marcel Dekker, 1995). Isolated site hydrates are hydrates in which water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, water molecules are located in lattice channels where they are adjacent to other water molecules. In metal ion coordination hydrate, water molecules are bound to metal ions.

  If the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. However, if the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be common.

  Multi-component complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts are also within the scope of the present invention. This type of complex includes clathrates (drug-host inclusion complexes) and co-crystals. The latter is usually defined as a crystalline complex of neutral molecular components that are linked via non-covalent interactions but can also be a complex of neutral molecules and salts. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. O. Almarsson and M.M. J. et al. See Chem Commun, 17, 1889-1896 (2004) by Zawortko. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288 (August 1975) by Halebrian.

The compounds of the present invention may exist in a mesomorphic state (mesophase or liquid crystal) when exposed to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism that occurs as a result of temperature changes is referred to as “therotropic”, and mesomorphism resulting from the addition of a second component, such as water or another solvent, is referred to as “lyotropic”. Compounds that have the potential to form lyotropic mesophases are referred to as “amphiphilic” and include ionic (—COO ⁻ Na ⁺ , —COO ⁻ K ⁺ , or —SO ₃ ⁻ Na ^+, etc. ) Or nonionic (such as —N ^— N ⁺ (CH ₃ ) ₃ ) polar head group. For more information, see N.C. H. Harthorne and A.H. See Crystals and the Polarizing Microscope by Stuart, 4th edition (Edward Arnold, 1970).

  Hereinafter, all references to compounds of formula (I) include their salts, solvates, multi-component complexes and liquid crystals, and solvates of those salts, multi-component complexes and liquid crystals. Includes mention.

  The compounds of the present invention include compounds of formula (I) as defined herein before, including all their polymorphs and crystal habits, their prodrugs and isomers as defined later herein. Isomers (including optical isomers, geometric isomers and tautomers) and isotopically labeled compounds of formula (I).

  As indicated, so-called “prodrugs” of the compounds of formula (I) are also within the scope of the invention. That is, certain derivatives of compounds of formula (I), which themselves may have little or no pharmacological activity, may have the desired activity when administered into the body or body surface, for example by hydrolysis. May be converted to a compound of formula (I). Such derivatives are referred to as “prodrugs”. Further information regarding the use of prodrugs can be found in Pro-drugs as Novell Delivery Systems, Volume 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug ss. In Roche, American Pharmaceutical Association).

  Prodrugs according to the invention can be prepared, for example, by suitable functional groups present in compounds of the formula (I) It can be prepared by replacing with a specific part known to the person skilled in the art as "pro-moieties" as described in Design of Prodrugs by Bundgaard (Elsevier, 1985).

Some examples of prodrugs according to the present invention include:
(I) When the compound of formula (I) contains a carboxylic acid functional group (—COOH), the ester, for example, hydrogen of the carboxylic acid functional group of the compound of formula (I) is (C ₁ -C _8). ) Compounds replaced by alkyl,
(Ii) when the compound of formula (I) contains an alcohol functional group (—OH), the ether, for example hydrogen of the alcohol functional group of the compound of formula (I), is (C ₁ -C ₆ ) alkanoyl Compounds replaced by oxymethyl,
(Iii) Where a compound of formula (I) contains a primary or secondary amino function (—NH ₂ or —NHR (R is not H)), its amide, eg, optionally formula (I) Compounds in which one or both hydrogens of the amino functionality of the compound are replaced by (C ₁ -C ₁₀ ) alkanoyl.

  Other examples of substituents according to the above examples and other prodrug type examples can be found in the above references.

  Furthermore, certain compounds of formula (I) can themselves act as prodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites of compounds of formula (1), ie, compounds formed in vivo upon administration of the drug. Some examples of metabolites according to the present invention include:
(I) when the compound of formula (I) contains a methyl group, its hydroxymethyl derivative (—CH ₃ → —CH ₂ OH),
(Ii) when the compound of formula (I) contains an alkoxy group, its hydroxy derivative (—OR → —OH),
(Iii) when the compound of formula (I) contains a tertiary amino group, its secondary amino derivative (—NR ¹ R ² → —NHR ¹ or —NHR ² ),
(Iv) when the compound of formula (I) contains a secondary amino group, its primary derivative (—NHR ¹ → —NH ₂ ),
(V) if the compound of formula (I) contains a phenyl moiety, the phenol derivative (-Ph → -PhOH), and (vi) if the compound of formula (I) contains a carboxamide group, Acid derivatives (—CONH ₂ → COOH) are included.

  Compounds of formula (1) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where the compound of formula (1) contains an alkenyl or alkenylene group, geometric cis / trans (ie, Z / E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (“tautomerism”) may occur. This may take the form of, for example, proton tautomerism in compounds of formula (I) containing imino, keto, or oxime groups, or so-called valence tautomerism in compounds containing aromatic moieties. As a result, a single compound may exhibit more than one type of isomerism.

  All stereoisomers, geometric isomers and tautomers of compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof are within the scope of the invention. include. Also included are acid addition or base salts in which the counterion is optically active, for example d-lactate or l-lysine, or racemic, for example dl-tartrate or dl-arginine.

  Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

  Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from appropriate optically pure precursors, or racemates (or salts using, for example, chiral high performance liquid chromatography (HPLC)). Or resolution of racemic derivatives).

  Alternatively, the racemate (or racemic precursor) can be converted to a suitable optically active compound, such as an alcohol, or 1-phenylethylamine or, if the compound of formula (I) contains an acidic or basic moiety, It can be reacted with a base or acid such as tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be separated by pure (single or single) by means well known to those skilled in the art. Can be converted to enantiomers.

  The chiral compounds of the present invention (and their chiral precursors) contain 0-50% by volume of isopropanol, typically 2% -20%, and 0-5% by volume of alkylamine, typically 0.1% diethylamine. It can be obtained in enantiomerically enriched form using chromatography on an asymmetric resin, typically HPLC, with a mobile phase consisting of hydrocarbons, typically heptane or hexane. Concentration of the eluate yields an enriched mixture.

  If any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) described above in which one homogeneous form of crystal is formed containing both enantiomers in equimolar amounts. The second type is a racemic mixture or aggregate in which two forms of crystals each containing a single enantiomer are formed in equimolar amounts.

  Although the crystals present in the racemic mixture both have the same physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art. For example, E.I. L. Eliel and S.M. H. See Stereochemistry of Organic Compounds (Wiley, 1994) by Wilen.

  The invention includes any pharmaceutically acceptable in which one or more atoms are replaced by an atom having the same atomic number but having an atomic weight or mass number that differs from the atomic weight or mass number that predominates in nature. Isotopically labeled compounds of formula (I) are included.

Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, ¹⁸ F and the like Fluorine, iodine such as ¹²³ I and ¹²⁵ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P, and sulfur isotopes such as ³⁵ S .

Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of the ease with which they are incorporated and the means to detect them.

Substitution with heavier isotopes, such as deuterium, ie ² H, may provide certain therapeutic benefits derived from greater metabolic stability, for example increased in vivo half-life or reduced dose requirements Therefore, it may be preferable in some environments.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.

  In general, isotope-labeled compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by using appropriate isotope-labeled reagents in place of the unlabeled reagents used so far. It can be prepared by processes analogous to those described in the examples and preparation.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D _{2 O,} d 6 _- acetone, is which may be solvate in d _6-DMSO It is.

  The compounds of formula (I) are alpha-2-delta receptor ligands and are potentially useful for the treatment of a wide range of disorders. Treatment of pain, particularly neuropathic pain, is a preferred use.

  Physiological pain is an important defense mechanism designed to warn of danger from potentially damaging stimuli from the outside environment. This system operates through a specific series of primary sensory neurons and is activated by noxious stimuli via a peripheral transmission mechanism (see Millan, 1999, Prog. Neurobio., 57, 1-164 for review). ). These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the location of the stimulus based on the intensity, duration and quality of the nociceptive stimulus and their topographically organized projection to the spinal cord. Nociceptors are found on nociceptive nerve fibers of which there are two main types, A-δ fibers (myelinated) and C fibers (unmyelinated). The activity generated by nociceptor input is transmitted to the basal ventral thalamus and then to the cortex, either directly or via the brainstem relay nucleus, after complex processing in the dorsal horn, where pain sensation is transmitted Generated.

  In general, pain can be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually 12 weeks or less). Acute pain usually has a specific cause, such as a specific injury, and is often sharp and severe. Acute pain is a type of pain that can occur after certain injuries resulting from surgery, dental treatment, a strain or a sprain. In general, acute pain does not result in any sustained psychological response. In contrast, chronic pain is long-term pain, usually lasting more than 3 months, leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (eg, painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, joint pain and chronic postoperative pain It is.

  When substantial damage occurs to body tissue through disease or trauma, the characteristics of nociceptor activation change, in the periphery, locally around the injury, where the nociceptor ends Centrally, there is sensitization. These effects lead to increased pain sensation. In acute pain, these mechanisms may be useful in promoting defensive behavior that may facilitate the repair process. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, hypersensitivity lasts much longer than the healing process and is often due to damage to the nervous system. This damage often leads to abnormalities in sensory nerve fibers associated with maladaptation and ectopic activity (Woolf and Salter, 2000, Science, 288, 1765-1768).

  Clinical pain is present when the patient's symptoms feature discomfort and abnormal sensitivity. Patients tend to be quite heterogeneous and may exhibit various pain symptoms. Such symptoms include 1) spontaneous pain such as blunting, burning pain, or stinging, 2) excessive pain response to noxious stimuli (hyperalgesia), and 3) pain caused by normally harmless stimuli Pain-Meyer et al., 1994, Textbook of Pain, 13-44). Patients suffering from various forms of acute and chronic pain have similar symptoms, but the underlying mechanisms may differ and may require different treatment strategies. Thus, pain can be classified into many different subtypes with different pathophysiology, including nociceptive, inflammatory and neuropathic pain.

  Nociceptive pain is induced by tissue damage or by intense stimuli that can cause damage. Pain afferents are activated by the transmission of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at their end positions. It is then relayed up the spinal tract to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). Activation of nociceptors activates two types of afferent nerve fibers. Myelinated A-δ fibers transmit quickly and carry a sharp and stinging pain sensation, while unmyelinated C fibers transmit at a slower rate and transmit blunt and aching pain. Moderate to severe acute nociceptive pain is CNS trauma, contusion / sprain, burn, myocardial infarction and acute pancreatitis, postoperative pain (pain after any type of surgery), posttraumatic pain, renal colic It is a distinguishing feature of pain from cancer pain and back pain. Cancer pain is chronic pain such as tumor-related pain (eg, bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (eg, post-chemotherapy syndrome, chronic postoperative pain syndrome or post-irradiation syndrome). It may be. Cancer pain may occur in response to chemotherapy, immunotherapy, hormone therapy or radiation therapy. Back pain can result from prolapsed or ruptured discs or abnormalities in the lumbar facet joint, sacroiliac joint, paraspinal muscle or posterior longitudinal ligament. Back pain may resolve naturally, but in some patients, if back pain lasts for 12 weeks, it becomes a chronic condition that can be particularly debilitating.

  Currently, neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Since nerve damage can be caused by trauma and disease, the term “neuropathic pain” encompasses many disorders with diverse etiologies. These include peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and chronic alcohol Includes, but is not limited to pain associated with addiction, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiencies. Neuropathic pain is pathological because it has no protective role. Neuropathic pain is often present even after the original cause has been resolved and generally persists for several years, significantly reducing the patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959- 1964). Symptoms of neuropathic pain are difficult to treat because they are often heterogeneous, even among patients with the same disease (Woolf and Decostard, 1999, Pain Sup., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353: 1959-1964). They include spontaneous pain, which can be persistent, and paroxysmal and abnormally induced pain such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally innocuous stimuli).

  The inflammatory process is a complex series of biochemical and cellular events that are activated in response to tissue damage or the presence of foreign bodies, resulting in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). ). Arthralgia is the most common inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory conditions in developed countries, and rheumatoid arthritis is a common cause of disability. Although the exact pathogenesis of rheumatoid arthritis is unknown, current hypotheses suggest that both genetic and microbiological factors may be important (Grennan and Jayson, 1994, Textbook of Pain, 397). ~ 407). It is estimated that nearly 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years old, It is expected to increase to 40 million people as age increases, and becomes a major public health problem (Houge and Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most osteoarthritis patients seek medical attention because of the associated pain. Arthritis has a major impact on psychosocial and physical functions and is known to be a major cause of disability in later years. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. Ankylosing spondylitis ranges from intermittent episodes of back pain that occur throughout life to severe chronic diseases that attack the spine, peripheral joints and other body organs.

  Another type of inflammatory pain is visceral pain, including pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, including the organs of the abdominal cavity. These organs include the reproductive organs, spleen and part of the digestive system. Pain related to the viscera can be classified as digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (GI) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IGD). These GI disorders include gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS) for FBD, Crohn's disease, ileitis and ulcerative colitis for IBD It includes a wide range of disease states that are currently only moderately managed, all of which regularly cause visceral pain. Other types of visceral pain include pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

  Some types of pain have multiple etiologies and can therefore be classified into more than one area, for example, back pain and cancer pain are both nociceptive and neuropathic components It should be noted that

For other types of pain,
Pain resulting from musculoskeletal disorders including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, dystrophin abnormalities, glycogenolysis, polymyositis and purulent myositis ,
Cardiac and vascular pain, including pain caused by angina, myocardial infarction, mitral stenosis, epicarditis, Raynaud's phenomenon, edematous sclerosis and skeletal muscle ischemia,
・ Headaches such as migraine (migraine with and without aura), cluster headache, tension-type headache, mixed headache and headache associated with vascular disorder, and ・ toothache, earache, oral burning Orofacial pain including syndrome and temporomandibular fascial pain is included.

  In addition to pain, the compounds of formula (I) are potentially useful for the treatment of any disease or condition that can be treated with alpha-2-delta receptor ligands. Such conditions include epilepsy, gastrointestinal disorders, premature ejaculation, oral fever syndrome, bladder disorders (such as overactive bladder), fainting attacks, fibromyalgia, hypokinetic movement, cranial disorders, thermal sensation, essential tremor, drugs Addiction and addiction, withdrawal symptoms associated with addiction or addiction, addiction, spasticity, arthritis, inflammatory disorders (eg, rheumatoid arthritis, osteoarthritis, psoriasis), diuresis, premenstrual syndrome, premenstrual dysphoric disorder, tinnitus, Stomach injury, Down syndrome, demyelinating diseases (eg, multiple sclerosis and amyotrophic lateral sclerosis), cerebrovascular disorders resulting from acute or chronic cerebrovascular injury (eg, cerebral infarction, subarachnoid hemorrhage or cerebral edema) ), Head trauma, spinal cord trauma and, for example, during a stroke, in cardiac bypass surgery, in an intracranial hemorrhage accident, in perinatal asphyxia, in cardiac arrest and in status epilepticus It includes nerve damage. Alpha-2-delta receptor ligands are associated with delirium, dementia and amnestic and other cognitive or neurodegenerative disorders (eg Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, memory impairment, vascular dementia) It may be useful in the treatment of Alpha-2-delta receptor ligands may be useful in the treatment of ataxia, movement disorders, spasticity, Tourette's syndrome, Scott syndrome, paralysis, akinetic stiffness syndrome and extrapyramidal movement disorders.

  Alpha-2-delta receptor ligands are associated with sleep disorders, mood disorders, depression, depressive disorders, bipolar disorder, anxiety disorders, panic, borderline personality disorder, schizophrenia, psychotic disorders, mental retardation It may be useful for the treatment of behavioral disorders, autistic disorders and behavioral disorders.

  All compounds of formula (I) may be prepared by procedures described in the General Methods set forth below, or by specific methods described in the Examples and Preparations sections, or methods analogous thereto. Can be prepared by conventional routes such as. The present invention also encompasses any one or more of these processes for preparing compounds of formula (I), in addition to any novel intermediates used herein.

In the following general methods, R ¹ , R ² , R ³ , R ⁴ and R ^4a are as previously defined for compounds of formula (I) unless otherwise specified.

  According to the first process, compounds of formula (I) can be prepared from compounds of formula (VIII) as illustrated by Scheme 1.

R ^a is a suitable acid protecting group, usually (C ₁ -C ₆ ) alkyl or benzyl, preferably benzyl.

R ^b is a suitable acid protecting group, usually (C ₁ -C ₆ ) alkyl.

  Y is T. W. Greene and P.M. Suitable 1,2-diol protecting groups as described in “Protecting Groups in Organic Synthesis” by Wutz.

When R ^4a is hydrogen, the compound of formula (II) is commercially available. When R ^4a is not hydrogen, the compounds of formula (II) are Bajwa and Miller (J. Org. Chem .; 1983; 48 (7); pages 1114 to 1116) and Eck and Simon (Tetrahedron; 1994; 50 ( 48); pages 13641 to 13654).

  The acetal compound of formula (III) W. Greene and P.M. It can be prepared from a compound of formula (II) by process step (i) using standard methodologies as described in “Protecting Groups in Organic Synthesis” by Wutz. Typical conditions include the use of 1.0 equivalent of diol compound (II) and 4.0 to 4.2 equivalents of 2,2-dimethoxypropane in toluene at a temperature of 40 to 80 ° C. for 1 to 8 hours. Including.

The compound of formula (IV) is prepared from process step (ii), ie the compound of formula (III) is O, O-diphenylphosphoryl in a suitable solvent such as toluene or xylene at a temperature of 80 ° C. to 150 ° C. It can be prepared from a compound of formula (III) by treatment with a suitable source of azide such as azide. The isocyanate intermediate is obtained by the Curtius rearrangement (Org. React. 1946, 3, 337) and treated in situ with a suitable alcohol (R ^a OH) to give a compound of general formula (IV). Typical conditions are followed by the use of 1.0 equivalent of compound of formula (III) and 1.2 equivalent of O, O-diphenylphosphoryl azide in toluene at a temperature of 80 ° C. to 150 ° C. for 1-4 hours. Treatment with R ^a OH in situ at a temperature between room temperature and 100 ° C. for 18-24 hours.

  The compound of formula (V) is prepared in process step (iii), ie in the presence of a suitable aqueous acid such as 1M hydrochloric acid or trifluoroacetic acid in a suitable solvent such as acetonitrile or dichloromethane under ambient conditions up to 18 hours. It can be prepared from a compound of formula (IV) by hydrolysis of a compound of formula (IV). Typical conditions include the use of 1.0 equivalent of a compound of formula (IV) in acetonitrile and excess dilute hydrochloric acid at room temperature for 18 hours.

  The compound of formula (VI) is converted into process step (iv), ie the compound of formula (V) is converted to a suitable alkyl such as trimethylsilyldiazomethane in a suitable solvent such as dichloromethane and methanol under ambient conditions for 1-18 hours. It can be prepared from a compound of general formula (V) by treatment with an agent. As an alternative method, the compound of formula (V) is deprotonated with a base such as sodium hydride and methyl iodide in a suitable solvent such as acetone at a temperature of 20 ° C. to 50 ° C. for 1 to 18 hours. Can be treated with an alkylating agent. Typical conditions include the use of 1.0 equivalent of the compound of formula (V) and 1.2 equivalent of trimethylsilyldiazomethane in a mixture of dichloromethane and methanol under ambient conditions up to 18 hours.

  In other embodiments, compounds of formula (VI) can be prepared from compounds of formula (IV) by a combination of process steps (iii) and (iv) in a one-pot synthesis.

  Compounds of formula (VII) are commercially available or can be prepared by standard methodologies known in the literature.

The compound of formula (VIII) is prepared according to process step (v), i.e. tri- ⁿ -butyl in a solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide at a temperature of 25-115 [deg.] C. for 1-48 hours. Between a compound of formula (VI) and a compound of formula (VII) in the presence of a suitable phosphine compound such as phosphine or triphenylphosphine and a suitable azo compound such as diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate. It can be prepared from the compound of general formula (VI) by Mitsunobu reaction. Typical conditions are 1.0 equivalent of compound of formula (VI), 1.0 to 1.30 equivalent of compound of formula (VII), 1.0 to 1.30 triphenylphosphine in tetrahydrofuran under ambient conditions for 18 hours. Including the use of 3 equivalents and 1.0-1.3 equivalents of di-tert-butyl azodicarboxylate.

  The compound of formula (I) is prepared according to process step (vi), i. W. Greene and P.M. It can be prepared from a compound of formula (VIII) by deprotection of the amino group and optionally the carboxyl group using standard methodologies as described in “Protecting Groups in Organic Synthesis” by Wutz. Typical conditions include treatment of 1.0 equivalent of a compound of formula (VIII) with excess concentrated acid such as 6N hydrochloric acid for up to 18 hours at a temperature between room temperature and 100 ° C.

  According to the second process, compounds of formula (I) can be prepared from compounds of formula (X) as described in Scheme 2.

R ^a , R ^b and Y are as defined above for Scheme 1.

  LG is a suitable leaving group such as mesylate or tosylate, preferably mesylate.

  Compounds of formula (VI) can be prepared as described for Scheme 1.

  The compound of formula (IX) is prepared in process step (vii), ie 1-6 hours at room temperature in a suitable solvent such as dichloromethane or diethyl ether in the presence of a suitable base such as Hunig's base, triethylamine or pyridine. Can be prepared from a compound of formula (VI) by introduction of a suitable leaving group LG such as mesylate or tosylate by reaction of a compound of formula (VI) with mesyl chloride / anhydride or tosyl chloride. Typical conditions include the use of 1.0 equivalent of a compound of formula (VI) in dichloromethane, 2.0 equivalents of methanesulfonic anhydride and 4.0 equivalents of triethylamine under ambient conditions of 1-6 hours.

  The compound of formula (X) is processed into process step (viii), ie the compound of formula (VII) is treated with a suitable strong base such as sodium hydride or potassium tert-butoxide and the resulting anion is converted to 1-18. Reaction with a compound of formula (IX) in a suitable solvent such as N, N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran at room temperature to the reflux temperature of the solvent for a period of time VII). Typical conditions are 1.3 equivalents of compound of formula (VII), 1.5-2.0 equivalents of sodium hydride, and 1.0 equivalent of compound of formula (IX) in tetrahydrofuran under ambient conditions up to 18 hours. Including the use of

  Compounds of formula (I) can be prepared from compounds of formula (X) by process step (vi) as described for scheme 1.

  The compound of formula (I) can be administered as a crystalline or amorphous product. The compound of formula (I) can be obtained by methods such as precipitation, crystallization, freeze-drying, spray-drying, or evaporation-drying, for example, as solid plugs, powders, or films. Microwave or radio frequency drying can be used for this purpose.

  The compounds of formula (I) can be used alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or as any combination thereof) ) Can be administered. Generally, the compound of formula (I) should be administered as a formulation with one or more pharmaceutically acceptable excipients. As used herein, the term “excipient” is used to describe any ingredient other than the compound (s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the influence of the excipient on solubility and stability, and the nature of the dosage form.

  Pharmaceutical compositions suitable for delivering the compounds of the present invention and methods for preparing them will be readily apparent to those skilled in the art. Such compositions and methods for preparing them can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

  The compounds of the present invention can be administered orally. Oral administration may include swallowing the compound into the gastrointestinal tract and / or buccal, lingual or sublingual administration where the compound enters the bloodstream directly from the mouth.

  Formulations suitable for oral administration include: tablets; soft or hard capsules containing multiparticulate or nanoparticulates, solutions or powders; lozenges (including liquids); chews; gels Fast dispersible dosage forms; films; vaginal suppositories; sprays; and solid / semi-solid and liquid systems such as buccal / mucoadhesive patches.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules (eg, made of gelatin or hydroxypropyl methylcellulose) and are usually carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or appropriate Oil, and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared, for example, from sachets by reconstitution of solids.

  The compounds of the present invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen's Expert Opinion in Therapeutic Patents, 11 (6), 981-986 (2001). Can do.

  For tablet dosage forms, depending on dosage, the drug may make up from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In general, tablets contain a disintegrant in addition to the drug. Examples of disintegrants include sodium starch glycolate, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch And sodium alginate. Generally, the disintegrant will comprise 1% to 25%, preferably 5% to 20% by weight of the dosage form.

  In general, binders are used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Also, tablets are diluted with lactose (monohydrate, spray dried monohydrate, anhydrous etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch and dicalcium phosphate dihydrate etc. An agent can be contained.

  Tablets may also contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, the surfactant may comprise from 0.2% to 5% by weight of the tablet and the glidant may comprise from 0.2% to 1% by weight of the tablet.

  Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Generally, the lubricant comprises 0.25% to 10%, preferably 0.5% to 3% by weight of the tablet.

  Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.

  Exemplary tablets include up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and lubricant From about 0.25% to about 10% by weight of the agent.

  Tablet blends can be compressed directly or by roller to make tablets. As an alternative, the tablet blend or part of the blend can be wet, dry, or melt granulated, melt-set, or extruded prior to tableting.

  The final formulation comprises one or more layers and may or may not be coated or encapsulated.

  Tablet formulation is described in H.C. Lieberman and L.L. Discussed in Lactman, Pharmaceutical Dosage Forms: Tablets, Volume 1 (Marcel Dekker, New York, 1980).

  Oral films that can be consumed for human or animal use are usually flexible water-soluble or water-swellable thin film dosage forms that may be fast dissolving or mucoadhesive and are usually of the formula ( Comprising compounds of I), film-forming polymers, binders, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents. Some components of the formulation may perform more than one function.

  The compound of formula (I) may be water-soluble or water-insoluble. Usually, the water-soluble compound comprises 1% to 80% by weight of the solute, more typically 20% to 50%. Less soluble compounds can account for a greater percentage of the composition, typically up to 88% by weight of the solute. As an alternative, the compound of formula (I) may be in the form of multiparticulate beads.

  The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is usually present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight.

  Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, co-solvents (including oils), emollients, fillers, antifoams, Surfactants as well as taste masking agents are included.

  Usually, the film according to the present invention is prepared by evaporating and drying a thin aqueous film coated on a peelable backing support or paper. This can be done in a drying oven or tunnel dryer, usually a composite coater dryer, or by freeze drying or vacuum suction.

  Solid formulations for oral administration can be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  Suitable modified release formulations for the purposes of the invention are described in US Pat. No. 6,106,864. Details of other suitable release technologies, such as high energy dispersants and osmotic and coated particles, can be found in Pharmaceutical Technology On-line, 25 (2), 1-14 (2001) by Verma et al. The use of chewing gum to achieve controlled release is described in WO 00/35298.

  The compounds of the present invention can also be administered directly into the bloodstream, muscle, or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) syringes, needleless syringes and infusion techniques.

  Typically, parenteral formulations are aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably a pH of 3-9), but for some applications, as sterile non-aqueous solutions Or more suitably formulated in dry form and used in conjunction with a suitable vehicle such as sterilized pyrogen-free water.

  Preparation of parenteral formulations under aseptic conditions, eg, by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

  The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques such as the incorporation of solubility enhancers.

  Formulations for parenteral administration can be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release. That is, the compounds of the present invention can be formulated as a suspension, or as a solid, semi-solid, or thixotropic liquid for administration as an implantable depot that provides controlled release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions including drug-loaded dl-lactic-glycolic acid (PGLA) microspheres. Contains turbidity agent.

  The compounds of the invention may also be administered topically, transdermally (intradermally), or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, dressings, foams, films, skin patches, wafers, implants, Sponges, fibers, bandages and microemulsions are included. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.

  Permeation enhancers can be incorporated. See, for example, J Pharm Sci, 88 (10), 955-958 (October 1999) by Finnin and Morgan.

  Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg Powderject ™, Bioject ™, etc.) injection .

  Formulations for topical administration can be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  The compounds of the invention may also be administered intranasally or by inhalation, usually from a dry powder inhaler to a dry powder (alone, for example, as a mixture in a dry blend with lactose or mixed with a phospholipid such as, for example, phosphatidylcholine). Use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane in the form of mixed component particles) Regardless, it can be administered as a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to generate a fine mist), or an aerosol spray from a nebulizer, or as a nasal spray. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers, or nebulizers may be used as, for example, ethanol, aqueous ethanol, or suitable alternative agents, solvents (one or more) for dispersion, solubilization, or extended release of the active substance. A) A solution or suspension of the compound (s) of the invention comprising a propellant and an optional surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be done by any suitable comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

  Capsules (eg, made of gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in inhalers or insufflators are suitable powder bases such as compounds of the invention, lactose or starch and l-leucine, mannitol, or stearin. It can be formulated to contain a powder mix of motion modifiers such as magnesium acid. Lactose may be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

  A solution formulation suitable for use in an atomizer using electrohydrodynamics to generate a fine mist can contain 1 μg to 20 mg of the compound of the invention per operation, with an operating volume from 1 μl to 100 μl. May change. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

  Appropriate flavors such as menthol and levomenthol, or sweeteners such as saccharin or saccharin sodium can be added to the formulations of the invention intended for inhalation / intranasal administration.

  Formulations for inhalation / intranasal administration can be formulated to be immediate release and / or modified release using, for example, PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a certain amount. Usually the units according to the invention are arranged to administer a certain amount or “puff”. The total daily dose can be administered as a single dose or, more generally, as divided doses throughout the day.

  The compounds of the present invention can be administered rectally or vaginally, for example, in the form of a suppository, vaginal suppository, or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as needed.

  Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  The compounds of the present invention may also be administered directly to the eye or ear, usually in the form of a finely divided suspension or solution drop in isotonic pH adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable (eg, absorbable gel sponges, collagen) and non-biodegradable (eg, silicone) implants, wafers, lenses. And microparticles or vesicle systems such as niosomes or liposomes. Cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum, together with preservatives such as benzalkonium chloride Can be incorporated. Such formulations can also be delivered by iontophoresis.

  Formulations for ocular / ear administration can be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  The compounds of the present invention can be combined with soluble polymers such as cyclodextrins and appropriate derivatives thereof or polyethylene glycol-containing polymers and their solubility, dissolution rate, taste masking for use in any of the aforementioned administration methods. Bioavailability and / or stability can be improved.

  For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with drugs, cyclodextrins can be used as auxiliary additives, ie carriers, diluents, or solubilizers. Α-, β- and γ-cyclodextrins are most commonly used for these purposes, examples of which are found in international patent applications WO 91/11172, WO 94/02518 and WO 98/55148. be able to.

  For administration to human patients, the total daily dose of the compounds of the invention is usually in the range of 1 mg to 1000 mg, depending of course on the method of administration. The total daily dose can be administered in a single dose or in divided doses and may deviate from the typical ranges shown herein at the physician's discretion.

  These dosages are based on an average human subject having a weight of about 60-70 kg. The physician should readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

  For the avoidance of doubt, references herein to “treatment” include curative, palliative and prophylactic treatment.

The alpha-2-delta receptor ligand can be usefully combined with another pharmacologically active compound or two or more other pharmacologically active compounds, particularly in the treatment of pain. For example, an alpha-2-delta receptor ligand as defined above, in particular a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,
Opioid analgesics such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalolphine, naloxone, naltrexone, Buprenorphine, butorphanol, nalbuphine or pentazocine,
Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, Miroxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylptazone, piroxicam, sulfasalazine, sulindac, tolmetine or zomepilac,
Barbitur sedatives, e.g. amobarbital, aprobarbital, butabarbital, butabital, mefobarbital, metalbital, methohexital, pentobarbital, phenobarbital, secobarbital, tarbutal, thiamylal or thiopental
Benzodiazepines with sedation, such as chlordiazepoxide, chlorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam,
H ₁ antagonists with sedative action, eg diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclidine,
Sedatives such as glutethimide, meprobamate, methacarone or dichlorphenazone,
Skeletal muscle relaxants such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orfrenazine
NMDA receptor antagonists such as NR2B antagonists such as ifenprodil, traxoprodil or (−)-(R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1 -Piperidinyl] -1-hydroxyethyl-3,4-dihydro-2 (1H) -quinolinone, dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ( (+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, budipine, EN-3231 (registered trademark) ), Morphine and dextromethorphan , Topiramate, neramexane or Perujinfoteru (perzinfotel),
Α-adrenergic agonists, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil or 4-amino-6,7-dimethoxy-2- (5-methane-sulfonamide-1,2, 3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline,
Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline,
Anticonvulsants such as carbamazepine, lamotrigine, topiramate or valproate,
Tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists such as (αR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9 , 10,11-Tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazosino [2,1-g] [1,7] naphthyridine-6-13-dione (TAK- 637), 5-[[(2R, 3S) -2-[(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] -Methyl] -1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, ranepitant, dapitant or 3-[[2-methoxy-5- (trifluoromethoxy) Phenyl]- Chiruamino] -2-phenylpiperidine (2S, 3S),
Muscarinic antagonists such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium,
A COX-2 selective inhibitor, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etlicoxib, or lumiracoxib,
Coal tar analgesics, especially paracetamol,
Dropperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, bronanserin, iloperidone, perospirone, laclopridone , Bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, parindole, eprivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan
A vanilloid receptor agonist (eg, resinferatoxin) or an antagonist (eg, capsazepine),
Β-adrenergic drugs such as propranolol,
・ Local anesthetics such as mexiletine,
Corticosteroids such as dexamethasone,
5-HT receptor agonists or antagonists, in particular 5-HT _{1B / 1D} agonists such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan,
-5-HT _2A receptor antagonism such as R (+)-α- (2,3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907) medicine,
Ispronicline (TC-1734), (E) -N-methyl-4- (3-pyridinyl) -3-buten-1-amine (RJR-2403), (R) -5- (2-azetidinylmethoxy) ) Cholinergic (nicotine-like) analgesics such as 2-chloropyridine (ABT-594) or nicotine;
-Tramadol (registered trademark),
5- [2-Ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one (sildenafil), (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -pyrazino [2 ′ , 1 ′: 6,1] -pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- (4-ethyl-piperazine-1- Yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one (Vardenafil), 5- (5-acetyl) -2-butoxy-3-pi Dinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- (5-acetyl-2-) Propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- [2- Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl) amino] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (pyrimidine-2- Ylmethyl) pyrimidine 5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- [2- (1- PDEV inhibitors such as methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide,
・ Cannabinoids,
-Metabotropic glutamate subtype 1 receptor (mGluR1) antagonist,
Sertraline, sertraline metabolite demethyl sertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolites desmethyl citalopram, escitalopram, d, l-fenfluramine, femoxetine, ifoxetine, ifoxetine (Cyanodothiepin), serotonin reuptake inhibitors such as ritoxetine, dapoxetine, nefazodone, cericlamin and trazodone,
Maprotiline, lofepramine, mirtazepine, oxaprotilin, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolites hydroxybuproprion, nomifensine and viloxazine (especially revalxin), Noradrenaline (norepinephrine) reuptake inhibitors, such as selective noradrenaline reuptake inhibitors such as (S, S) -reboxetine,
Dual serotonin-noradrenaline reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolites desmethylclomipramine, duloxetine, milnacipran and imipramine,
S- [2-[(1-Iminoethyl) amino] ethyl] -L-homocysteine, S- [2-[(1-Iminoethyl) -amino] ethyl] -4,4-dioxo-L-cysteine, S -[2-[(1-Iminoethyl) amino] ethyl] -2-methyl-L-cysteine, (2S, 5Z) -2-amino-2-methyl-7-[(1-iminoethyl) amino] -5 Heptenoic acid, 2-[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -butyl] thio] -5-chloro-3-pyridinecarbonitrile; 2-[[(1R , 3S) -3-Amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -4-chlorobenzonitrile, (2S, 4R) -2-amino-4-[[2-chloro-5- (Trifluoromethyl) phenyl] thio] 5-thiazolebutanol, 2-[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -6- (trifluoromethyl) -3pyridinecarbonitrile, 2- [[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -5-chlorobenzonitrile, N- [4- [2- (3-chlorobenzylamino) ethyl ] Inducible nitric oxide synthase (iNOS) inhibitors such as phenyl] thiophene-2-carboxamidine or guanidinoethyl disulfide,
Acetylcholinesterase inhibitors such as donepezil,
N-[({2- [4- (2-Ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl} amino) -carbonyl] -4- Prostaglandin E ₂ such as methylbenzenesulfonamide or 4-[(1S) -1-({[5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid Subtype 4 (EP4) antagonist,
1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- Leukotriene B4 antagonists such as (4-methoxyphenyl) -5E-hexenyl] oxyphenoxy] -valeric acid (ONO-4057) or DPC-11870,
Zileuton, 6-[(3-fluoro-5- [4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]) phenoxy-methyl] -1-methyl-2-quinolone ( ZD-2138), or 5-lipoxygenase inhibitors such as 2,3,5-trimethyl-6- (3-pyridylmethyl), 1,4-benzoquinone (CV-6504),
Sodium channel blockers such as lidocaine,
-5-HT3 antagonists such as ondansetron,
And one or more agents selected from pharmaceutically acceptable salts and solvates thereof, and can be administered simultaneously, sequentially or individually.

  When administering a combination of active compounds, two or more pharmaceutical compositions can be conveniently combined in the form of a kit suitable for co-administration of the composition. Such a kit comprises two or more separate pharmaceutical compositions, at least one containing an alpha-2-delta receptor ligand, in particular a compound of formula (I), and a container, separate bottle, or separate Means for holding the composition separately, such as foil packets. An example of such a kit is the well-known blister pack used for the packaging of tablets, capsules and the like.

  Such kits are particularly suitable for different dosage forms, e.g. oral and parenteral formulations, to administer separate compositions at different dosing intervals or to increase separate compositions relative to each other. Yes. To assist compliance, the kit typically includes instructions for administration and can provide so-called memory assistance.

It is to be understood that what is provided by the present invention and what is recited in the claims is as follows.
(I) a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof,
(Ii) a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use as a medicament,
(Ii) use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a disease for which an alpha-2-delta receptor ligand is indicated;
(Iii) use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of pain;
(Iv) a method of treating a disease or condition for which an alpha-2-delta receptor ligand is indicated in a mammal, including a human, comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or Administering a solvate comprising:
(V) a method of treating pain in mammals, including humans, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,
(Vi) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable excipient;
(Vii) a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof;
(Viii) certain novel intermediates disclosed herein, and (ix) combinations of a compound of formula (I) with one or more other pharmacologically active compounds.

  The following examples illustrate the preparation of compounds of formula (I).

¹ H nuclear magnetic resonance (NMR) spectra were consistent with the predicted structure in all cases. The characteristic chemical shift (δ) is a conventional abbreviation for representing the main peak, eg, s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; br Using a wide range, tetramethylsilane is shown in parts per million from low magnetic fields. Mass spectra (MS) were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). The following abbreviations were used for common solvents. CDCl _{3, deuterochloroform;} D 6 -DMSO, deuterated dimethyl sulfoxide; _CD 3 OD, deuteromethanol; THF, tetrahydrofuran. LCMS indicates liquid chromatography mass spectrometry (R _t = retention time).

(Example 1)
3-Amino-2-[(1-ethylpropyl) thio] propanoic acid hydrochloride

調製７の生成物（４９ｍｇ、０．１４ｍｍｏｌ）と６Ｎ塩酸（１５ｍＬ）の混合物を還流下で１８時間加熱した。次いで、反応混合物を室温まで冷却し、ジクロロメタン（４×２０ｍＬ）で洗浄し、真空中で濃縮すると、収率４６％で白色の固体として表題化合物１５ｍｇが得られた。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ：０．９９〜１．０２（ｍ，６Ｈ）、１．５５〜１．８０（ｍ，４Ｈ）、２．８４〜２．８１（ｍ，１Ｈ）、３．１５〜３．２０（ｍ，１Ｈ）、３．３１〜３．３６（ｍ，１Ｈ）、３．５８〜３．６２（ｍ，１Ｈ）；ＬＲＭＳ ＥＳＩ ｍ／ｚ １９２［Ｍ＋Ｈ］^＋

A mixture of the product of Preparation 7 (49 mg, 0.14 mmol) and 6N hydrochloric acid (15 mL) was heated at reflux for 18 hours. The reaction mixture was then cooled to room temperature, washed with dichloromethane (4 × 20 mL) and concentrated in vacuo to give 15 mg of the title compound as a white solid in 46% yield.
¹ HNMR (400 MHz, CD ₃ OD) δ: 0.99 to 1.02 (m, 6H), 1.55 to 1.80 (m, 4H), 2.84 to 2.81 (m, 1H), 3.15-3.20 (m, 1H), 3.31-3.36 (m, 1H), 3.58-3.62 (m, 1H); LRMS ESI m / z 192 [M + H] ⁺

(Examples 2 to 8)
The following compounds of the general formula shown below were prepared from the products of Preparations 5 and 8-13 using the same method as described for Example 1.

Preparation 1
[(4R) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] acetic acid

２，２−ジメトキシプロパン（７５ｍＬ、６１０ｍｍｏｌ）を、トルエン（２００ｍＬ）中のＤ（＋）リンゴ酸（１９．８ｇ、１４８ｍｍｏｌ）の溶液に加え、混合物を還流下で２．５時間加熱した。反応混合物を真空中で濃縮し、残渣を、ジエチルエーテルで溶出するシリカゲル上のカラムクロマトグラフィーにより精製した。適切な分画を減圧下で蒸発させ、残渣を、ヘプタン：ジエチルエーテル、６６：３３〜５０：５０〜０：１００で溶出するシリカゲル上のカラムクロマトグラフィーによりさらに精製すると、収率７９％で表題化合物２０．２ｇが得られた。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．５８（ｓ，３Ｈ）、１．６３（ｓ，３Ｈ）、２．８０〜３．０５（ｍ，２Ｈ）、４．７０（ｍ，１Ｈ）

2,2-Dimethoxypropane (75 mL, 610 mmol) was added to a solution of D (+) malic acid (19.8 g, 148 mmol) in toluene (200 mL) and the mixture was heated at reflux for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with diethyl ether. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel eluting with heptane: diethyl ether, 66: 33-50: 50-0: 100 to give the title in 79% yield. 20.2 g of compound was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 1.58 (s, 3H), 1.63 (s, 3H), 2.80 to 3.05 (m, 2H), 4.70 (m, 1H)

Preparation 2
{[(4R) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] methyl} benzyl carbamate

トルエン（１００ｍＬ）中の調製１の生成物（９．８ｇ、５６ｍｍｏｌ）、トリエチルアミン（９．４１ｍＬ、６８ｍｍｏｌ）およびＯ，Ｏ−ジフェニルホスホリルアジド（１３．３４ｍＬ、６１．６ｍｍｏｌ）の混合物を８５℃にて９０分間加熱した。次いで、ベンジルアルコール（６．４３ｍＬ、６２ｍｍｏｌ）を加え、加熱を、８５℃にて２０時間続けた。冷却した反応混合物を真空中で濃縮し、残渣を、ジクロロメタン（２００ｍＬ）と水（１００ｍＬ）の間で分配した。有機層を分離し、ブライン（１００ｍＬ）で洗浄し、合わせた水溶液をジクロロメタン（２００ｍＬ）で抽出した。合わせた有機溶液を炭酸水素ナトリウム溶液で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮した。残渣を、ジクロロメタンで溶出するシリカゲル上のカラムクロマトグラフィーにより精製した。適切な分画を減圧下で蒸発させ、残渣を、ヘプタン：酢酸エチル、７５：２５〜６６：３３で溶出するシリカゲル上のカラムクロマトグラフィーによりさらに精製すると、収率３５％で油として表題化合物５．４９ｇが得られた。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．５４（ｓ，３Ｈ）、１．５６（ｓ，３Ｈ）、３．５５〜３．７２（ｍ，２Ｈ）、４．４６〜４．４９（ｍ，１Ｈ）、５．０５〜５．１６（ｍ，２Ｈ）、７．３１〜７．３６（ｍ，５Ｈ）；ＬＣＭＳ ｍ／ｚ ２８０［Ｍ＋Ｈ］^＋

A mixture of the product of Preparation 1 (9.8 g, 56 mmol), triethylamine (9.41 mL, 68 mmol) and O, O-diphenylphosphoryl azide (13.34 mL, 61.6 mmol) in toluene (100 mL) to 85 ° C. For 90 minutes. Benzyl alcohol (6.43 mL, 62 mmol) was then added and heating was continued at 85 ° C. for 20 hours. The cooled reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (200 mL) and water (100 mL). The organic layer was separated and washed with brine (100 mL) and the combined aqueous solution was extracted with dichloromethane (200 mL). The combined organic solution was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel eluting with heptane: ethyl acetate, 75:25 to 66:33 to give the title compound 5 as an oil in 35% yield. .49 g was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 1.54 (s, 3H), 1.56 (s, 3H), 3.55 to 3.72 (m, 2H), 4.46 to 4.49 (m , 1H), 5.05 to 5.16 (m, 2H), 7.31 to 7.36 (m, 5H); LCMS m / z 280 [M + H] ⁺

Preparation 3
(2R) -3-{[(Benzyloxy) carbonyl] amino} -2-hydroxypropanoic acid

アセトニトリル（８０ｍＬ）中の調製２の生成物（４．２９ｇ、１５ｍｍｏｌ）の溶液を、１Ｍ塩酸（８０ｍＬ）で処理し、混合物を室温にて１８時間撹拌した。次いで、反応混合物を真空中で低容量まで濃縮し、混合物を濾過し、水で十分に洗浄した。残渣をアセトン（１００ｍＬ）に溶かし、溶液を５分間撹拌し、濾過した。濾液をトルエンで希釈し、真空中で濃縮すると、収率８３％で白色の固体として表題化合物２．９７ｇが得られた。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ：３．３３〜３．４０（ｍ，１Ｈ）、３．５０〜３．５５（ｍ，１Ｈ）、４．２０〜４．２３（ｍ，１Ｈ）、５．０８（ｓ，２Ｈ）、７．２７〜７．３４（ｍ，５Ｈ）；ＬＣＭＳ ｍ／ｚ ２３８［Ｍ＋Ｈ］^＋

A solution of the product of Preparation 2 (4.29 g, 15 mmol) in acetonitrile (80 mL) was treated with 1M hydrochloric acid (80 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo to a low volume and the mixture was filtered and washed thoroughly with water. The residue was dissolved in acetone (100 mL) and the solution was stirred for 5 minutes and filtered. The filtrate was diluted with toluene and concentrated in vacuo to give 2.97 g of the title compound as a white solid in 83% yield.
¹ HNMR (400 MHz, CD ₃ OD) δ: 3.33 to 3.40 (m, 1H), 3.50 to 3.55 (m, 1H), 4.20 to 4.23 (m, 1H), 5.08 (s, 2H), 7.27-7.34 (m, 5H); LCMS m / z 238 [M + H] ⁺

Preparation 4
(2R) -3-{[(Benzyloxy) carbonyl] amino} -2-hydroxypropanoic acid methyl ester

トリメチルシリルジアゾメタン（ヘキサン中２Ｍ、３９．５７ｍＬ、７９．１４ｍｍｏｌ）を、ジクロロメタン（４８０ｍＬ）およびメタノール（１２０ｍＬ）中の調製３の生成物（１５．７８ｇ、６５．６５ｍｍｏｌ）の溶液に加え、混合物を室温にて１８時間撹拌した。次いで、反応混合物を真空中で濃縮し、残渣を酢酸エチル（２００ｍＬ）に溶かし、希酢酸溶液（２００ｍＬ）およびブライン（２００ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮した。ヘプタン：酢酸エチル、５０：５０〜０：１００で溶出するシリカゲル上のカラムクロマトグラフィーにより残渣を精製すると、収率７７％で黄色の固体として表題化合物１２．９ｇが得られた。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：３．５０〜３．６２（ｍ，２Ｈ）、３．７７（ｓ，３Ｈ）、４．２７〜４．３０（ｍ，１Ｈ）、５．０９（ｓ，２Ｈ）、５．１８〜５．２７（ｍ，１Ｈ）、７．２９〜７．３５（ｍ，５Ｈ）；ＬＣＭＳ ｍ／ｚ ２５４［Ｍ＋Ｈ］^＋

Trimethylsilyldiazomethane (2M in hexane, 39.57 mL, 79.14 mmol) is added to a solution of the product of Preparation 3 (15.78 g, 65.65 mmol) in dichloromethane (480 mL) and methanol (120 mL) and the mixture is added to room temperature. For 18 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL), washed with dilute acetic acid solution (200 mL) and brine (200 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with heptane: ethyl acetate, 50:50 to 0: 100 to give 12.9 g of the title compound as a yellow solid in 77% yield.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 3.50 to 3.62 (m, 2H), 3.77 (s, 3H), 4.27 to 4.30 (m, 1H), 5.09 (s , 2H), 5.18-5.27 (m, 1H), 7.29-7.35 (m, 5H); LCMS m / z 254 [M + H] ⁺

Preparation 5
(2S) -3-{[(Benzyloxy) carbonyl] amino} -2-[(3-chlorophenyl) thio] propanoic acid methyl ester

アゾジカルボン酸ジ−イソプロピル（３１９ｍｇ、１．５８ｍｍｏｌ）を、テトラヒドロフラン（４ｍＬ）中のトリフェニルホスフィン（４１４ｍｇ、１．５８ｍｍｏｌ）の氷冷溶液に加え、混合物を室温にて３０分間撹拌した。次いで、調製４の生成物（２００ｍｇ、０．７９ｍｍｏｌ）および３−クロロベンゼンチオール（１１９μＬ、１．０３ｍｍｏｌ）を加え、混合物を室温にて４８時間撹拌した。次いで、反応混合物を水（数滴）でクエンチし、真空中で濃縮した。残渣を酢酸エチルに溶かし、１Ｍ水酸化ナトリウム溶液（１０ｍＬ）およびブライン（１０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥し、真空中で濃縮した。ヘプタン：酢酸エチル、８３：１７、７５：２５で溶出するシリカゲル上のカラムクロマトグラフィーにより残渣を精製すると、収率３４％で白色の固体として表題化合物１０２ｍｇが得られた。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：３．４３〜３．５８（ｍ，２Ｈ）、３．６４（ｓ，３Ｈ）、３．８１〜３．８４（ｍ，１Ｈ）、５．０１（ｓ，２Ｈ）、５．０９〜５．１８（ｍ，１Ｈ）、７．１６〜２９（ｍ，８Ｈ）、７．３９（ｓ，１Ｈ）；ＬＣＭＳ ｍ／ｚ ３８０［Ｍ＋Ｈ］^＋

Di-isopropyl azodicarboxylate (319 mg, 1.58 mmol) was added to an ice-cold solution of triphenylphosphine (414 mg, 1.58 mmol) in tetrahydrofuran (4 mL) and the mixture was stirred at room temperature for 30 minutes. The product of Preparation 4 (200 mg, 0.79 mmol) and 3-chlorobenzenethiol (119 μL, 1.03 mmol) were then added and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then quenched with water (a few drops) and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M sodium hydroxide solution (10 mL) and brine (10 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with heptane: ethyl acetate, 83:17, 75:25 to give 102 mg of the title compound as a white solid in 34% yield.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 3.43 to 3.58 (m, 2H), 3.64 (s, 3H), 3.81 to 3.84 (m, 1H), 5.01 (s , 2H), 5.09-5.18 (m, 1H), 7.16-29 (m, 8H), 7.39 (s, 1H); LCMS m / z 380 [M + H] ⁺

Preparation 6
(2R) -3-{[(Benzyloxy) carbonyl] amino} -2-[(methylsulfonyl) oxy] methyl propanoate

メタンスルホン酸無水物（２．５３ｇ、１４．５ｍｍｏｌ）を、ジクロロメタン（２０ｍＬ）中の調製４の生成物（１．８４ｇ、７．３ｍｍｏｌ）およびトリエチルアミン（４．０５ｍＬ、２９．１ｍｍｏｌ）の氷冷溶液に加え、混合物を室温にて３時間撹拌した。次いで、反応混合物を、酢酸エチル（８０ｍＬ）と水（４０ｍＬ）の間で分配し、有機層を分離し、硫酸マグネシウムで乾燥し、真空中で濃縮した。ヘプタン：酢酸エチル、６６：３３〜５０：５０で溶出するシリカゲル上のカラムクロマトグラフィーにより残渣を精製すると、収率８６％で表題化合物２．０７ｇが得られた。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：３．１２（ｓ，３Ｈ）、３．６０〜３．６７（ｍ，１Ｈ）、３．７５〜３．８２（ｍ，１Ｈ）、３．７８（ｓ，３Ｈ）、５．１０（ｓ，２Ｈ）、５．１３〜５．１５（ｍ，１Ｈ）、５．２４〜５．３０（ｍ，１Ｈ）、７．２９〜７．３７（ｍ，５Ｈ）；ＬＣＭＳ ｍ／ｚ ３５４［Ｍ＋Ｈ］^＋

Add methanesulfonic anhydride (2.53 g, 14.5 mmol) to the ice-cooled product of Preparation 4 (1.84 g, 7.3 mmol) and triethylamine (4.05 mL, 29.1 mmol) in dichloromethane (20 mL). To the solution, the mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate (80 mL) and water (40 mL) and the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with heptane: ethyl acetate, 66:33 to 50:50, to give 2.07 g of the title compound in 86% yield.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 3.12 (s, 3H), 3.60 to 3.67 (m, 1H), 3.75 to 3.82 (m, 1H), 3.78 (s 3H), 5.10 (s, 2H), 5.13-5.15 (m, 1H), 5.24-5.30 (m, 1H), 7.29-7.37 (m, 5H) LCMS m / z 354 [M + H] ⁺

Preparation 7
3-{[(Benzyloxy) carbonyl] amino} -2-[(1-ethylpropyl) thio] propanoic acid methyl ester

水素化ナトリウム（鉱油中６０％分散液、２５ｍｇ、１．０４ｍｍｏｌ）を、テトラヒドロフラン（４ｍＬ）中の調製１４の生成物（８２ｍｇ、０．７８ｍｍｏｌ）の溶液に加え、混合物を、発泡が止むまで室温にて撹拌した。次いで、反応混合物を０℃まで冷却し、次いで、テトラヒドロフラン（１ｍＬ）中の調製６の生成物（２００ｍｇ、０．６ｍｍｏｌ）の溶液を加え、混合物を室温にて９０分間撹拌した。次いで、混合物をジクロロメタン（４０ｍＬ）と水（４０ｍＬ）の間で分配し、有機層を分離し、硫酸マグネシウムで乾燥し、真空中で濃縮した。残渣を、ペンタン：ジクロロメタン、３３：６６〜０：１００で溶出するＩｓｏｌｕｔｅシリカカートリッジを用いるカラムクロマトグラフィーにより精製すると、収率２４％で表題化合物４９ｍｇが得られた。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：０．９４〜０．９８（ｍ，６Ｈ）、１．５１〜１．６７（ｍ，４Ｈ）、２．６７〜２．７３（ｍ，１Ｈ）、３．４７〜３．５４（ｍ，３Ｈ）、３．７３（ｓ，３Ｈ）、５．０５〜５．１４（ｍ，２Ｈ）、５．２０〜５．２８（ｍ，１Ｈ）、７．３０〜７．３６（ｍ，５Ｈ）；ＬＲＭＳ ＥＳＩ ｍ／ｚ ３６２［Ｍ＋Ｎａ］^＋

Sodium hydride (60% dispersion in mineral oil, 25 mg, 1.04 mmol) is added to a solution of the product of Preparation 14 (82 mg, 0.78 mmol) in tetrahydrofuran (4 mL) and the mixture is allowed to come to room temperature until bubbling stops. Was stirred at. The reaction mixture was then cooled to 0 ° C., then a solution of the product of Preparation 6 (200 mg, 0.6 mmol) in tetrahydrofuran (1 mL) was added and the mixture was stirred at room temperature for 90 minutes. The mixture was then partitioned between dichloromethane (40 mL) and water (40 mL) and the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using an Isolute silica cartridge eluting with pentane: dichloromethane, 33:66 to 0: 100, to give 49 mg of the title compound in 24% yield.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 0.94 to 0.98 (m, 6H), 1.51 to 1.67 (m, 4H), 2.67 to 2.73 (m, 1H), 3 .47 to 3.54 (m, 3H), 3.73 (s, 3H), 5.05 to 5.14 (m, 2H), 5.20 to 5.28 (m, 1H), 7.30 ˜7.36 (m, 5H); LRMS ESI m / z 362 [M + Na] ⁺

Preparation 8-13
The following compounds of the general formula shown below are prepared using the product of Preparation 6 with the appropriate thiol starting material (commercially available or prepared as described below) and the method described for Preparation 7: Prepared using the same method.

Preparation 14
Pentane-3-thiol

チオ尿素（３．０３ｇ、４０ｍｍｏｌ）を、エタノール（４０ｍＬ）中の３−ブロモペンタン（５ｇ、３３ｍｍｏｌ）の溶液に加え、混合物を還流下で２時間加熱した。次いで、反応混合物を室温まで冷却し、真空中で濃縮した。残渣を水（３０ｍＬ）に溶かし、５Ｍ水酸化ナトリウム溶液（１５ｍＬ、７５ｍｍｏｌ）を加え、混合物を室温にて１８時間撹拌した。反応混合物を１５％硫酸で酸性化し、ペンタン（１００ｍＬ）と水（５０ｍＬ）の間で分配した。有機層を分離し、硫酸マグネシウムで乾燥し、真空中で濃縮すると、収率５％で表題化合物２００ｍｇが得られた。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：０．９７〜１．０１（ｍ，６Ｈ）、１．３０〜１．３２（ｍ，１Ｈ）、１．４４〜１．５５（ｍ，２Ｈ）、１．６２〜１．７４（ｍ，２Ｈ）、２．６２〜２．７０（ｍ，１Ｈ）

Thiourea (3.03 g, 40 mmol) was added to a solution of 3-bromopentane (5 g, 33 mmol) in ethanol (40 mL) and the mixture was heated under reflux for 2 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (30 mL), 5M sodium hydroxide solution (15 mL, 75 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was acidified with 15% sulfuric acid and partitioned between pentane (100 mL) and water (50 mL). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give 200 mg of the title compound in 5% yield.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 0.97 to 1.01 (m, 6H), 1.30 to 1.32 (m, 1H), 1.44 to 1.55 (m, 2H), 1 .62 to 1.74 (m, 2H), 2.62 to 2.70 (m, 1H)

Preparation 15
2-Ethylbutane-1-thiol

表題化合物１．３６ｇは、収率３８％で油として、調製１４について記載されている方法と同じ方法を用い、１−ブロモ−２−エチルブタンおよびチオ尿素から調製した。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：０．８４〜０．８８（ｍ，６Ｈ）、１．１５〜１．１９（ｍ，１Ｈ）、１．３４〜１．４３（ｍ，５Ｈ）、２．５１〜２．５５（ｍ，２Ｈ）。

The title compound 1.36 g was prepared from 1-bromo-2-ethylbutane and thiourea as an oil in 38% yield using the same method as described for Preparation 14.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 0.84 to 0.88 (m, 6H), 1.15 to 1.19 (m, 1H), 1.34 to 1.43 (m, 5H), 2 51-2.55 (m, 2H).

The biological activity of the alpha-2-delta ligand of the present invention is determined by [ ³ H] gabapentin and α ₂ δ subunits derived from porcine brain tissue (Gee NS, Brown JP, Disanayake VU). , K., Offer J., Thrlow R., Woodruff GN, J. Biol. Chem., 1996; 271; 5768-5776). Results can be expressed as μM or nM α2δ binding affinity.

All the examples described above were tested in this alpha-2-delta assay and found to have a binding affinity (IC ₅₀ ) of 140 nM or less.

Claims (11)

A compound of formula I,

Or a pharmaceutically acceptable salt or solvate thereof,
[Where:
R ¹ is hydrogen or (C ₁ -C ₆ ) alkyl;
R ² is
a) (C ₂ -C ₆ ) alkyl optionally substituted by one or more substituents R ³ ,
b) phenyl, naphthyl or benzyl each substituted by one or more substituents R ³ , and c) optionally substituted by one or more substituents R ³ (C ₃ -C ₈ ) Selected from cycloalkyl,
Each R ³ is independently halogen, cyano, nitro, amino, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) Alkynyl, hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkoxy, Halo (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylamino, (di- (C ₁ -C ₆ ) alkyl) amino, amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) Alkylamino (C ₁ -C ₆ ) alkyl, (di- (C ₁ -C ₆ ) alkyl) amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) _{acyloxy, (C} 1 _{~C 6)} acyloxy _(C 1 ~C _{6) alkyl, (C} 1 _{~C 6) acylamino, (C} 1 _{~C 6) alkylthio, (C} 1 _{~C 6) alkylthiocarbonyl, (C} 1 _{~C 6)} alkylsulfonyl, _{(C 1} -C ₆₎ alkylsulfonylamino, _{aminosulfonyl, (C} 1 -C ₆₎ alkylaminosulfonyl, (di - _(C 1 -C ₆₎ alkyl) _{aminosulfonyl, (C} 3 -C ₈₎ cycloalkyl, ^Het 1, Selected from phenyl and Het ² ;
Het ¹ is a 5- or 6-membered saturated or partially unsaturated heterocyclic group containing 1 or 2 heteroatom ring members each independently selected from nitrogen, oxygen and sulfur, wherein the ring nitrogen The atom may have a (C ₁ -C ₆ ) alkyl substituent, the ring sulfur atom may have 1 or 2 oxygen atoms,
Het ² is a 5- or 6-membered heteroaryl containing either (a) 1 to 4 nitrogen atoms or (b) 1 oxygen or 1 sulfur atom and 0, 1 or 2 nitrogen atoms Group,
R ⁴ and R ^4a are independently hydrogen or methyl]
Provided that the compound is a compound of formula I which is neither 3-amino-2- (ethylthio) -propanoic acid nor S-trityl-DL-isocysteine, or a pharmaceutically acceptable salt or solvate thereof. R ² is
a) (C ₂ -C ₆ ) alkyl optionally substituted by one or more substituents R ³ ,
b) phenyl substituted by one or more substituents R ³ , and c) selected from (C ₃ -C ₈ ) cycloalkyl optionally substituted by one or more substituents R ³ A compound of formula (I) according to claim 1. Each R ³ is independently halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkoxy and halo. _(C 1 -C ₆₎ compounds of formula (I) according to claim 1 or claim 2 is selected from alkylthio. The compound of formula (I) according to any one of claims 1 to 3, wherein R ¹ is hydrogen. A compound of formula (I) according to any one of claims 1 to 4, wherein R ⁴ and R ^4a are both hydrogen. (2S) -3-amino-2-[(1-ethylpropyl) thio] propanoic acid,
(2S) -3-amino-2-[(3-chlorophenyl) thio] propanoic acid,
(2S) -3-amino-2-[(1-methylethyl) thio] propanoic acid,
(2S) -3-amino-2-[(t-butyl) thio] propanoic acid,
(2S) -3-amino-2-[(2-methylpropyl) thio] propanoic acid,
(2S) -3-amino-2-[(2-ethylbutyl) thio] propanoic acid,
(2S) -3-amino-2-[(cyclopentyl) thio] propanoic acid,
(2S) -3-amino-2-[(cyclohexyl) thio] propanoic acid,
And a compound of formula (I) according to claim 1 selected from pharmaceutically acceptable salts and solvates thereof.   7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.   7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of pain.   Use of a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of pain.   A medicament comprising a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. Composition. A method of treating pain in mammals, including humans, comprising an effective amount of a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof. A method comprising administering.